Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:To assess the strength of evidence for associations between environmental toxicants and hypertensive disorders of pregnancy, suggest potential biological mechanisms based on animal and in vitro studies, and highlight avenues for future research. RECENT FINDINGS/RESULTS:Evidence is strongest for links between persistent chemicals, including lead, cadmium, organochlorine pesticides, and polycyclic biphenyls, and preeclampsia, although associations are sometimes not detectable at low-exposure levels. Results have been inconclusive for bisphenols, phthalates, and organophosphates. Biological pathways may include oxidative stress, epigenetic changes, endocrine disruption, and abnormal placental vascularization. Additional prospective epidemiologic studies beginning in the preconception period and extending postpartum are needed to assess the life course trajectory of environmental exposures and women's reproductive and cardiovascular health. Future studies should also consider interactions between chemicals and consider nonlinear associations. These results confirm recommendations by the International Federation of Gynecology and Obstetrics, the American Society for Reproductive Medicine, the American Academy of Pediatrics, and the Endocrine Society that providers counsel their pregnant patients to limit exposure to environmental toxicants.

OBJECTIVES/OBJECTIVE:To compare lung function in a representative sample of World Trade Center (WTC)-exposed children with matched comparisons, and examine relationships with reported exposures. STUDY DESIGN/METHODS:Study population consisted of 402 participants. Oscillometry, spirometry, and plethysmography were performed on WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 (n = 180) and a sociodemographically matched group of New York City residents (n = 222). We compared lung function by study arm (WTCHR and comparison group) as well as dust cloud (acute); home dust (subchronic); and other traumatic, nondust exposures. RESULTS:In multivariable models, post-9/11 risk of incident asthma was higher in the WTCHR participants than in the comparison group (OR 1.109, 95% CI 1.021, 1.206; P = .015). Comparing by exposure rather than by group, dust cloud (OR 1.223, 95% CI 1.095, 1.365; P < .001) and home dust (OR 1.123, 95% CI 1.029, 1.226; P = .009) exposures were also associated with a greater risk of incidence of post-9/11 asthma. No differences were identified for lung function measures. CONCLUSIONS:Although we cannot exclude an alternative explanation to the null findings, these results may provide some measure of reassurance to exposed children and their families regarding long-term consequences. Further study with bronchodilation and/or methacholine challenge may be needed to identify and further evaluate effects of WTC exposure. Biomarker studies may also be more informative in delineating exposure-outcome relationships. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov: NCT02068183.

Background/UNASSIGNED:Increasing evidence suggests that exposure to synthetic chemicals such as bisphenols and phthalates can influence fecundability. The current study describes associations of first trimester urinary concentrations of bisphenol A (BPA), BPA analogues and phthalate metabolites with time to pregnancy (TTP). Methods/UNASSIGNED:Among 877 participants in the population-based Generation R pregnancy cohort, we measured first trimester urinary concentrations of bisphenols and phthalates (median gestational age 12.9 weeks [inter-quartile range 12.1-14.4 weeks]). We used fitted covariate-adjusted Cox proportional hazard models to examine associations of bisphenol and phthalate concentrations with TTP. Participants who conceived using infertility treatment were censored at 12 months. Biologically plausible effect measure modification by folic acid supplement use was tested. Results/UNASSIGNED:In the main models, bisphenol and phthalate compounds were not associated with fecundability. In stratified models, total bisphenols and phthalic acid were associated with longer TTP among women who did not use folic acid supplements preconceptionally (respective fecundability ratios per each natural log increase were 0.90 [95% Confidence Interval (CI) 0.81, 1.00] and 0.88 [95% CI 0.79, 0.99]). Using an interaction term for the exposure and folic acid supplement use showed additional effect measure modification by folic acid supplement use for high molecular weight phthalate metabolites. Conclusions/UNASSIGNED:We found no associations of bisphenols and phthalates with fecundability. Preconception folic acid supplementation seems to modify effects of bisphenols and phthalates on fecundability. Folic acid supplements may protect against reduced fecundability among women exposed to these chemicals. Further studies are needed to replicate these findings and investigate potential mechanisms.

BACKGROUND:Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. METHODS:We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. RESULTS:Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings. CONCLUSIONS:Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.

BACKGROUND:Exposure to air pollution during pregnancy may increase attention-deficit/ hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS:Air pollution concentrations [nitrogen dioxide (NO2) and particulate matter (PM)] were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cut-offs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputation and applied inverse probability weighting methods to correct for loss to follow-up. RESULTS:We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio (OR) for ADHD symptoms of 0.95, 95% confidence interval (CI) 0.89-1.01 per 10µg/m increase in NO2 and 0.98, 95%CI 0.80-1.19 per 5µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS:There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3 to 10 years.

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959-1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (B = -2.51, 99% CI: -4.84,-0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = -1.28, 99% CI: -2.49,-0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children.

BACKGROUND:The collapse of the World Trade Center (WTC) on September 11, 2001 released a dust cloud containing numerous environmental contaminants, including polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans (PCDD/Fs). PCDD/Fs are toxic and are associated with numerous adverse health outcomes including cancer, diabetes, and impaired reproductive and immunologic function. Prior studies have found adults exposed to the WTC disaster to have elevated levels of PCDD/Fs. This is the first study to assess PCDD/F levels in WTC-exposed children. METHODS:This analysis includes 110 participants, a subset of the 2014-2016 WTC Adolescent Health Study, a group of both exposed youths who lived, attended school, or were present in lower Manhattan on 9/11 recruited from the WTC Health Registry (WTCHR) and unexposed youths frequency matched on age, sex, race, ethnicity, and income. Our sample was selected to maximize the contrast in their exposure to dust from the WTC collapse. Questionnaire data, including items about chronic home dust and acute dust cloud exposure, anthropometric measures, and biologic specimens were collected during a clinic visit. Serum PCDD/F concentrations were measured according to a standardized procedure at the New York State Department of Health Organic Analytical Laboratory. We used multivariable linear regression to assess differences in PCCD/Fs between WTCHR and non-WTCHR participants. We also compared mean and median PCDD/F and toxic equivalency (TEQ) concentrations in our cohort to 2003-4 National Health and Nutrition Examination Survey (NHANES) levels for youths age 12-19. RESULTS:Median PCDD/F levels were statistically significantly higher among WTCHR participants compared to non-WTCHR participants for 16 out of 17 congeners. Mean and median TEQ concentrations in WTCHR participants were >7 times those in non-WTCHR participants (72.5 vs. 10.1 and 25. 3 vs. 3.39pg/g lipid, respectively). Among WTCHR participants, median concentrations of several PCDD/Fs were higher than the NHANES 95th percentiles. After controlling for dust cloud exposure, home dust exposure was significantly associated with higher PCDD/F level. CONCLUSIONS:Adolescents in lower Manhattan on the day of the WTC attack and exposed to particulate contamination from the WTC collapse had significantly elevated PCDD/F levels >12years later compared to a matched comparison group, driven by chronic home dust exposure rather than acute dust cloud exposure. PCDD/F and TEQ levels substantially exceeded those in similar-aged NHANES participants. Future studies are warranted to explore associations of PCDD/Fs with health and developmental outcomes among individuals exposed to the WTC disaster as children.

BACKGROUND:Exposure to bisphenols and phthalates in pregnancy may lead to adverse health effects in women themselves and their offspring. OBJECTIVE:To describe first trimester bisphenol and phthalate urine concentrations, including bisphenol and phthalate replacements, and determine nutritional, socio-demographic and lifestyle related determinants. METHODS:In a population-based prospective cohort of 1396 mothers, we measured first trimester bisphenol, phthalate and creatinine urine concentrations (samples collected in 2004-2005, median gestational age 12.9 weeks [inter-quartile range (IQR) 12.1-14.4]). We examined associations of potential determinants with log-transformed bisphenol and phthalate concentrations. Outcomes were back-transformed. Nutritional analyses were performed in a subgroup of 642 Dutch participants only, as the Food Frequency Questionnaire was aimed at Dutch food patterns. RESULTS:Bisphenol A, bisphenol S, and bisphenol F were detected in 79.2%, 67.8% and 40.2% of the population, respectively. Mono-n-butylphthalate, mono-(2-ethyl-5-hydroxyhexyl)phthalate and monobenzylphthalate were detected in > 90% of the population. Nutritional intake was not associated with bisphenol and phthalate concentrations after correction for multiple testing was applied. Obesity was associated with higher high-molecular-weight phthalate concentrations and the lack of folic acid supplement use with higher di-n-octylphthalate concentrations (respective mean differences were 46.73nmol/l [95% CI 14.56-93.72] and 1.03nmol/l [0.31-2.06]). CONCLUSION/CONCLUSIONS:Bisphenol S and F exposure was highly prevalent in pregnant women in the Netherlands as early as 2004-5. Although associations of dietary and other key factors with bisphenol and phthalate concentrations were limited, adverse lifestyle factors including obesity and the lack of folic acid supplement use seem to be associated with higher phthalate concentrations in pregnant women. The major limitation was the availability of only one urine sample per participant. However, since phthalates are reported to be quite stable over time, results concerning determinants of phthalate concentrations are expected to be robust.

BACKGROUND AND OBJECTIVE: In utero exposure to perfluorooctanoic acid (PFOA) has been associated with decreases in birth weight. We aimed to estimate the proportion of PFOA-attributable low birth weight (LBW) births and associated costs in the US from 2003 to 2014, a period during which there were industry-initiated and regulatory activities aimed at reducing exposure. METHODS: Serum PFOA levels among women 18-49 years were obtained from the National Health and Nutrition Examination Survey (NHANES) for 2003-2014; birth weight distributions were obtained from the Vital Statistics Natality Birth Data. The exposure-response relationship identified in a previous meta-analysis (18.9g decrease in birth weight per 1ng/mL of PFOA) was applied to quantify PFOA-attributable LBW (reference level of 3.1ng/mL for our base case, 1 and 3.9ng/mL for sensitivity analyses). Hospitalization costs and lost economic productivity were also estimated. RESULTS: Serum PFOA levels remained approximately constant from 2003-2004 (median: 3.3ng/mL) to 2007-2008 (3.5ng/mL), and declined from 2009-2010 (2.8ng/mL) to 2013-2014 (1.6ng/mL). In 2003-2004, an estimated 12,764 LBW cases (4% of total for those years) were potentially preventable if PFOA exposure were reduced to the base case reference level (10,203 cases in 2009-2010 and 1,491 in 2013-2014). The total cost of PFOA-attributable LBW for 2003 through 2014 was estimated at $13.7 billion, with $2.97 billion in 2003-2004, $2.4 billion in 2009-2010 and $347 million in 2013-2014. CONCLUSIONS: Serum PFOA levels began to decline in women of childbearing age in 2009-2010. Declines were of a magnitude expected to meaningfully reduce the estimated incidence of PFOA-attributable LBW and associated costs.